Successful malaria prevention, control and elimination activities depend on the sustained application of effective and well-targeted interventions. Developing innovative approaches and establishing novel applications of established approaches requires multi-disciplinary research. The research should be carried out in sites which span the ecological spectrum in which malaria thrives. Close coordination with policy makers enhances the transition from data to policy. Malawi, a landlocked country in southern Africa, is the ideal setting for transformative malaria research. Malawi contains within its boundaries nearly all of the eco-geographic settings relevant to malaria control. Malaria research in Malawi has been ongoing for over 20 years, and is concentrated in its one medical school, the University of Malawi College of Medicine. The National Malaria Control Program, the relevant policy-making body in Malawi, has made a series of data driven decisions, and its link with investigators in the College of Medicine is strong. The Malawi ICEMR will harness all of these advantages to establish a self-sustaining research entity capable of developing the scientific basis for designing, implementing, and evaluating malaria control and prevention strategies. Core activities (Administrative, Data Management and Biostatistics, and Molecular and Genomic) will be based in the College of Medicine, and research activities will take place in 3 epidemiologically diverse sites, all located within 50 kilometers of each other. The primary objectives of the research are to identify, understand and evaluate interventions that target the determinants of malaria disease. We will accomplish these objectives by systematically surveying populations of vectors, hosts and parasites using newly developed molecular and genomic tools in conjunction with well-established epidemiologic approaches. Four synergistic Projects (two in the area of epidemiology, and two in transmission) are described. Through existing and new communication channels we will ensure that research findings are brought to bear on policy development. The surveillance mechanisms established during this work will provide a mechanism for determining the impact of those policies on malaria infection and disease.